KR100431039B1 - The crystalline form III [R- (R *, R *)] - 2- (4-fluorophenyl) -beta delta-dihydroxy-5- Phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid hemicalcium salt (atorvastatin) - Google Patents

Abstract

(R ^* , R ^* )] - 2- (4-fluorophenyl) - ?,? - dihydroxy-5- (Phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid hemicalcium salt is characterized by its X-ray powder diffraction and / or solid state NMR and is characterized by its preparation method and the treatment of hyperlipemia and hypercholesterolemia ≪ / RTI > is disclosed.

Description

Crystalline form III [R- (R *, R *)] - 2- (4-fluorophenyl) -beta delta-dihydroxy-5- Phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid hemicalcium salt (atorvastatin)

The invention chemical name ^{[R- (R *, R *} )] - 2- ( 4-fluorophenyl) - β, δ - dihydroxy-5- (1-methylethyl) -3-phenyl-4- [ (Phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid hemicalcium salt, which is useful as a medicament, a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier, And a pharmaceutical treatment method. The novel crystalline compounds of the present invention are useful as inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and are therefore useful as antihistamines and anticholesterol.

U.S. Patent No. 4,681,893, incorporated herein by reference, discloses a process for the preparation of trans (±) -5- (4-fluorophenyl) -2- (1-methylethyl) -N, Yl) ethyl] -1H-pyrrole-3-carboxamide, which comprises the reaction of a specific trans-6- [2- (3- or 4- Pyrrol-1-yl) alkyl] -4-hydroxy-pyran-2-one.

U.S. Patent No. 5,273,995, incorporated herein by reference, discloses a process for the preparation of trans-5- (4-fluorophenyl) -2- (1-methylethyl) -N, Yl) ethyl] -1H-pyrrole-3-carboxamide, that is to say the [R- (R ^* , R ^* R ^* )] - 2- (4-fluorophenyl) - ?,? - dihydroxy-5- (1-methylethyl) -1-heptanoic acid.

U.S. Patent Nos. 5,003,080, 5,097,045, 5,103,024, 5,124,482, 5,149,837, 5,155,251, 5,216,174, 5,245,047, 5,248,793, 5,280,126, 5,397,792 and 5,342,952 disclose various methods and critical intermediates for the preparation of atorvastatin.

Atorvastatin is a calcium salt thereof, i.e., [R- (R ^* , R ^* )] - 2- (4-fluorophenyl) - ?,? - dihydroxy- Carbonyl] -1H-pyrrole-1-heptanoic acid calcium salt (2: 1). Calcium salts are preferred because they make it possible to formulate atorvastatin in conventional formulations, such as tablets, capsules, lozenges, powders and other oral preparations. In addition, there is a need to produce atorvastatin in a pure crystalline form that allows formulation to be tailored to exacting pharmaceutical requirements and specifications.

Moreover, the method by which atorvastatin is produced should be suitable for mass production. In addition, the product is required to be in a form that is easily filtered and easily dried. Finally, it is economically desirable that the product be stable for extended periods of time without requiring special storage conditions.

The methods in the above US patents disclose amorphous atorvastatin which must be protected from heat, light, oxygen and moisture with filtration and drying properties unsuitable for mass production.

The inventors have surprisingly and unexpectedly discovered that atorvastatin can be prepared in a crystalline form. Thus, the present invention provides a new crystalline form of atorvastatin designated as type III. The new crystalline type atorvastatin designated as Type I, Type II and Type IV is disclosed in Korean Patent Application Nos. 1998-700346 and Korean Patent Application No. 2002-7017608 (Korean Patent Application No. 1998-700346; Both patent applications are based on International Publication No. WO 97/03958). Crystalline Form III atorvastatin has different physical properties than conventional amorphous products.

SUMMARY OF THE INVENTION

Accordingly, the invention is 2θ, d- spacings, and CuK _α measured on a Siemens (Siemens) D-500 diffractometer, according to the research> below, expressed in terms of relative intensities with a relative intensity of 25% X-ray powder diffraction Lt; RTI ID = 0.0 > III < / RTI > type atorvastatin and a hydrate thereof.

Moreover, the present invention relates to crystalline Form III atorvastatin and its hydrates characterized by the following solid state ¹³ C nuclear magnetic resonance spectrum, wherein chemical shifts are expressed in ppm measured on a Bruker AX-250 spectrometer.

Since it is an inhibitor of HMG-CoA, the new crystalline forms of atorvastatin are useful as antihistamines and anticholesterol.

A further aspect of the present invention is a pharmaceutical composition for the administration of an effective amount of crystalline type III atorvastatin in unit dosage form in the above-mentioned treatment methods. Finally, the invention relates to a process for the preparation of type III atorvastatin.

The present invention is further illustrated by the following non-limiting embodiments, with reference to the accompanying drawings, Figs. 1-2, briefly described below.

1

The diffraction pattern of type III atorvastatin (Y axis = 0 to maximum intensity of 2815 cps)

2

Solid-state ¹³ C nuclear magnetic resonance spectrum of type III atorvastatin with rotating side band identified by star

Crystalline Form III atorvastatin is characterized by its X-ray powder diffraction pattern and / or its solid state nuclear magnetic resonance spectrum (NMR).

≪ X-ray powder diffraction &

Type III atorvastatin

Form III atorvastatin is characterized by its X-ray powder diffraction pattern. Therefore, X-ray diffraction pattern of the type III atorvastatin was measured in Siemens (Siemens) D-500 diffractometer using CuK in _a survey.

equipment

Siemens D-500 Diffractometer with IBM Compatibility Interface - Kristalloflex, DIFFRACAT (SOCABIM 1986, 1992).

Kane IBEX profile between Peltier kuldeu (Kevex Psi Peltier Cooled) Silicon [Si (Li)] Detector (grid: in 1 ° in the III and 0.15 ° IV) to electronically CuK _a research filtered by (20 mA, 40 kV, λ = 1.5406 A) (lattice I and II at 1 DEG)

Way

Silicon standards run daily to check the X-ray tube alignment.

Continuous θ / 2 θ coupled scan: 4.00 ° to 40.00 ° at 2 θ , scan rate at 6 ° / min: 0.4 sec / 0.04 ° step.

The sample was placed in a vial and pressed onto a zero point image in an aluminum holder. Sample width 13-15 mm.

The samples were stored at room temperature and operated.

Table 1 shows the relative intensities of all lines in the fine grinding the sample with a relative intensity of> 25% for the 2 θ, d- spacings, and the crystalline form III of atorvastatin. It should also be appreciated that the number of computer generated and unrotated figures is shown in this table.

[Table 1]

The intensity and peak position of all diffraction lines with relative intensities of at least 25% relative to type III atorvastatin

Solid State Nuclear Magnetic Resonance (NMR)

Way

All solid state ¹³ C NMR measurements were performed using a Bruker AX-250, 250 MHz NMR spectrometer. High resolution spectra were obtained at about 5 kHz using high power quantum decoupling and cross polarity (CP) by magic angle rotation (MAS). Frye JS and Maciel GE, J. Mag. Res., 1982; 48: 125], the Br signal for KBr was used to adjust the magic angle. A sample of about 300-450 mg filled into a rotor designed as a canister was used for each experiment. Chemical shifts were referenced to external tetrakis (trimethylsilyl) silane (methyl signal at 3.50 ppm) (see Muntean JV and Stock LM, J. Mag. Res., 1988; 76: 54).

Table 2 shows the solid state NMR spectrum for crystalline type III atorvastatin.

[Table 2]

Designation and chemical transfer of carbon atoms to type III atorvastatin

The crystalline Form III atorvastatin of the present invention may exist in anhydrous and hydrated forms. The hydrated form is generally in a non-hydrated form and is within the scope of the present invention.

The present invention also provides a method for preparing crystalline type III atorvastatin comprising exposing atorvastatin to high relative humidity under conditions that produce crystalline type III atorvastatin.

The precise conditions under which crystalline Form III atorvastatin is formed can be determined empirically, and only this can provide a method found to be practically suitable.

Thus, for example, the starting material is commonly assigned to the assignee of the present application, the entirety of which is assigned to the assignee of the present application, PD-5250-01-FJT, Serial No. 08/945, 812, U.S. Patent No. 5,969,156, Crystalline (R- (R ^* , R ^* )] - 2- (4-fluorophenyl) -beta delta-dihydroxy-5- (Also crystalline forms I and IV atorvastatin) disclosed in U.S. Patent Application, entitled " Carbonyl] -1H-pyrrole-1-heptanoic acid hemicalcium salt (atorvastatin) Crystalline type III atorvastatin can be produced by exposing solids to 95% relative humidity for 11 days.

Crystalline type II atorvastatin may be prepared from a combination of amorphous, amorphous and crystalline type I atorvastatin or crystalline type I atorvastatin. Thus, for example, if the starting material is a combination of amorphous, amorphous, and I forms, or crystalline Form I atorvastatin, the desired crystalline Form II atorvastatin is converted to the desired form in methanol containing from about 40% to about 50% Suspending the solid until complete, and then filtering.

Crystalline Form I atorvastatin can be prepared by crystallization under controlled conditions. In particular, this may be accomplished by adding a calcium salt, such as calcium acetate, from an aqueous solution of a corresponding basic salt such as, for example, an alkali metal salt such as lithium, potassium, sodium or the like, ammonia or an amine salt, preferably a sodium salt or by suspending the amorphous atorvastatin in water . Generally, it is preferred to use a hydroxyl alkaline, such as a lower alkanol, such as, for example, methanol.

The compounds of the present invention can be manufactured and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the invention may be administered by injection, i. E., Intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally or intraperitoneally. The compounds of the present invention may also be administered by inhalation, such as into the nose. In addition, the compounds of the present invention can be administered percutaneously. It will be apparent to one skilled in the art that the following dosage forms may contain the compounds of the present invention or the pharmaceutically acceptable salts corresponding to the present compounds as the active ingredient.

For the production of a pharmaceutical composition from a compound of the present invention, the pharmaceutically acceptable carrier may be a solid or a liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier may also be one or more substances which may act as diluents, flavors, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials.

In powders, the carrier is a particulate solid and is present in admixture with the particulate active component.

In tablets, the active ingredient is mixed with the carrier having the requisite binding properties in suitable proportions and compacted in the shape and size desired.

The powders and tablets preferably contain 2 to 10% to about 70% of the active ingredient. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and the like. The term " agent " is intended to include a combination of an active compound with an encapsulating material as a carrier, with or without other carriers, wherein the active ingredient is surrounded by the carrier and thus provides a capsule to which it is bound. Likewise caches and rosin maps are included. Tablets, powders, capsules, pills, cachets and rosin can be used as solid dosage forms suitable for oral administration.

In the preparation of suppositories, low melting waxes such as a mixture of fatty acid glycerides or cocoa butter are first melted and the active ingredient is homogeneously dispersed therein, as by stirring. The molten homogeneous mixture is poured into a mold of a conventional size and cooled to solidify.

Liquid form preparations include solutions, suspensions, static enemas and emulsions such as, for example, water or water propylene glycol solutions. In parenteral injection, the liquid preparation can be formulated in a solution state in an aqueous solution of polyethylene glycol.

Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers and thickeners, if necessary.

Aqueous suspensions suitable for oral use can be prepared by dispersing the particulate active ingredient in water containing viscous substances such as natural or synthetic rubbers, resins, methylcellulose, sodium carboxymethylcellulose, and other known suspending agents.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active ingredients, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.

Pharmaceutical formulations are preferably unit dosage forms. In such form, the agent is divided into unit doses containing the appropriate amount of the active ingredient. The unit dosage form can be a packaged preparation, which contains a separate amount of preparation, such as a pack of tablets, capsules, and powders in a vial or ampoule. The unit dosage form may itself be a capsule, tablet, cachet, or rosin, or the appropriate number of any of these may be present in a packaged form.

The amount of the active ingredient in the unit dosage form may be varied or adjusted to 0.5 mg to 100 mg, preferably 2.5 mg to 80 mg depending on the specific indication and the potency of the active ingredient. If desired, the composition may also contain other coexistent therapeutic agents.

In therapeutic applications as antihistamines and / or anticholesterol, the crystalline Form III atorvastatin used in the pharmaceutical method of the present invention is administered from about 2.5 mg to about 80 mg per day for the initial administration. A daily dosage range of from about 2.5 mg to about 20 mg is preferred. However, the dosage varies depending on the needs of the patient, the severity of the disease to be treated and the compound used. Determination of a suitable dosage for a particular situation is made by the prior art in the art. In general, the treatment begins with a dose less than the optimal dose of the compound. Thereafter, the dose is increased by small increments until the best efficacy is achieved in that situation. For convenience, the total daily dose may be administered divided into portions of the day if desired.

The following non-limiting examples illustrate our preferred methods for the preparation of compounds of the present invention.

≪ Example 1 >

[R- (R ^* , R ^* )] - 2- (4-fluorophenyl) - β, δ (I-form atorvastatin) salt of hemi-calcium salt of dihydroxy-5- (1-methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1H-

(2R-trans) -5- (4-fluorophenyl) -2- (1-methylethyl) -N, 4-diphenyl- 1- [2- (tetrahydro- (75 kg), methyl t-butyl ether (MTBE) (308 kg), methanol (5 ml) 190 L) was reacted with sodium hydroxide aqueous solution (950 L to 5.72 Kg) at 48-58 C for 40-60 minutes to form the ring-opened sodium salt. After cooling to 25-35 [deg.] C, the organic layer was discarded and the aqueous layer was extracted again with MTBE (230 kg). The organic layer was discarded and an aqueous solution of the MTBE-saturated sodium salt was heated to 47-52 [deg.] C. To this solution was added a solution of calcium acetate hemihydrate (11.94 kg) dissolved in water (410 L) over 30 minutes. Immediately after adding the calcium acetate solution, a slurry of crystalline type I atorvastatin (1.1 l of water and 1.1 l of 5 l of methanol) was added to the mixture as a crystal source. The mixture was heated to < RTI ID = 0.0 > 51-57 C < / RTI > for at least 10 minutes and then cooled to 15-40C. The mixture was filtered and washed with a solution of water (300 L) and methanol (150 L) followed by water (450 L). The solids were dried under vacuum at 60-70 [deg.] C for 3-4 days to yield crystalline Form I atorvastatin (72.2 kg).

≪ Example 2 >

[R- (R ^* , R ^* )] - 2- (4-fluorophenyl) - β, δ -Heptanoic acid hemi-calcium salt (type II atorvastatin) was used in place of dihydroxy-5- (1-methylethyl)

A mixture of amorphous and crystalline type I atorvastatin (100 g) was suspended in a mixture of methanol (1200 ml) and water (800 ml) and stirred for 3 days. This material was filtered and dried at 70 [deg.] C under reduced pressure to produce crystalline Form II atorvastatin.

≪ Example 3 >

[R- (R ^* , R ^* )] - 2- (4-fluorophenyl) - β, δ -Heptanoic acid hemi-calcium salt (type III atorvastatin) was used as the starting material.

Type II atorvastatin (Example 2) was rotapted onto a 100 mesh screen through a 50 mesh screen and exposed in a wet slurry at 95% relative humidity for 11 days to produce crystalline type III atorvastatin.

Claims (8)

CuK _α of at least the crystalline form III of atorvastatin to one or more having a X- ray powder diffraction with 2 θ values measured with the irradiation [R- (R *, R * )] - 2- ( 4-fluorophenyl) - Beta, delta-dihydroxy-5- (1-methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid hemicalcium salt) hydrate: 16.619 or 19.984. CuK _α crystalline form III of atorvastatin to the at least one or more measured by a survey having a X- ray powder diffraction with 2 θ values hydrate: 16.619, 19.984 and 20.294. CuK _α crystalline form III of atorvastatin to the at least one or more measured by a survey having a X- ray powder diffraction with 2 θ values hydrate: 8.451, 16.619 and 24.405. CuK _α crystalline form III of atorvastatin to the at least one or more measured by a survey having a X- ray powder diffraction with 2 θ values hydrate: 4.123, 4.993, 5.768, 7.670, 8.451, 15.962, 16.619, 17.731, 18.267, 18.870, 19.480, 19.984, 20.294, 21.105, 21.670, 23.318, 24.405, 24.967 and 25.397. Crystalline type III atorvastatin hydrate characterized by solid state ¹³ C nuclear magnetic resonance with a chemical shift difference of 7.1 or 165.0 between the minimum ppm resonance and the other resonance. Crystalline Form III atorvastatin hydrate characterized by solid state ¹³ C nuclear magnetic resonance with the following chemical shift differences between minimum ppm resonance and other resonances: 2.2, 4.2, 7.1, 45.7, 47.4 and 165.0. Crystalline type III atorvastatin hydrate characterized by solid state ¹³ C nuclear magnetic resonance with the following chemical shift differences between minimum ppm resonance and other resonances: 2.2, 4.2, 7.1, 15.5, 20.5, 24.2, 45.7, 47.4, 49.9, 95.0 , 97.3, 102.3, 104.4, 109.0, 111.9, 115.3, 120.2, 141.1, 146.8 and 165.0 Crystalline type III atorvastatin hydrate characterized by solid state ¹³ C nuclear magnetic resonance with the following chemical shifts expressed in ppm: 19.9, 22.1, 24.1, 27.0, 35.4, 40.4, 44.1, 65.6, 67.3, 69.8, 114.9, 117.2, 122.2, 124.3, 128.9, 131.8, 135.2, 140.1, 161.0, 166.7 and 184.9.